Method of therapeutic administration of dhe to enable rapid relief of migraine while minimizing side effect profile

ABSTRACT

Pharmaceutical compositions containing dihydroergotamine (DHE) and methods in which DHE is administered to patients for treatment of migraine without side effects or adverse effects are disclosed. Methods for rapid treatment of migraine with DHE are disclosed comprising: dampening the peak plasma concentration (C max ) and slightly delaying the peak such as to avoid activating the dopaminergic and adrenergic receptors, while achieving sufficient active binding to the serotonin receptors to provide relief from migraine symptoms within a timeframe that permits rapid resolution of migraine symptoms. Inhaler devices suitable for the methods are disclosed. Kits for practicing the methods of invention are disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/921,860, filed on Oct. 23, 2015, which is continuation of U.S. patentapplication Ser. No. 14/514,322, filed on Oct. 14, 2014, which is acontinuation of U.S. patent application Ser. No. 13/406,391, filed onFeb. 27, 2012, which is a continuation of U.S. patent application Ser.No. 12/069,667, filed on Feb. 11, 2008, which issued as U.S. Pat. No.8,148,377 on Apr. 3, 2012, which claims priority to U.S. ProvisionalApplication Ser. No. 60/900,850, filed on Feb. 11, 2007, the entirecontents of each of which is hereby incorporated by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to methods for treatment of migraine. Inparticular, the present invention relates to methods for treatment ofmigraine and related symptoms while minimizing side-effects, or adverseeffects, associated with administration of medications that alleviatemigraine symptoms. More specifically, the invention relates topharmaceutical compositions containing dihydroergotamine (DHE) andmethods in which these pharmaceutical compositions are administered topatients for the treatment of migraine headaches without side effects.

BACKGROUND OF THE INVENTION

Migraine is the most common headache causing patients to consult aphysician. According to the American Migraine Study II, approximately 28million people in the United States aged 12 and older (approximately 13percent of the population) suffer from headaches that fit the medicaldefinition of migraine established by the International HeadacheSociety. This corresponds to one migraine sufferer in every four U.S.households. The percentage of patients whose headaches fit the medicaldefinition of migraine who are being diagnosed has increased compared toa decade ago. A majority of all migraine sufferers (53 percent)characterize their pain as causing either severe impairment or forcingthem to retreat to their beds sometimes for days at a time. There havebeen no dramatic changes in the way physicians approach the treatment ofmigraine in the past 10 years. (Lipton R B. et al., Headache, (2001)41:638-645, 646-657)

A three-item Identification of Migraine (ID Migraine) clinical decisionrule for the diagnosis of migraine has been developed. (Stewart W F etal., Neurology 1994; 44 (6 suppl 4):S17-23.) A migraine is a type ofprimary headache that some people get repeatedly over time. Migrainesare different from other headaches because they occur with symptoms suchas nausea, vomiting, or sensitivity to light. In most people, athrobbing pain is felt only on one side of the head. Migraines areclassified as either “with aura” or “without aura.” An aura is a groupof neurological symptoms, usually vision disturbances that serve aswarning sign. Patients who get auras typically see a flash of brightlycolored or blinking lights shortly before the headache pain begins.However, most people with migraines do not have such warning signs.

Multiple humoral agents have been postulated as being the major factorin migraine. These include serotonin, histamine, prostaglandins,platelet factors, endorphins, and vasoactive neuropeptides. The etiologyof migraine has been studied by many investigators. Present research nolonger fully supports the vasodilator/vasoconstrictor mechanism ofvascular headache, i.e., arterial dilation causes pain and constrictionequals relief. Research also has now implicated a sterile inflammation,possibly occurring in the dura mater, as the causative factor forvascular head pain. An unknown trigger activates perivascular trigeminalaxons, which release vasoactive neuropeptides (substance P, calcitoningene-related peptide, etc.). These agents produce the local inflammationi.e., vasodilation, plasma extravasation, mast cell degranulation whichcause transmission of impulses to the brain stem and higher centerswhich in turn register as head pain (Moskowitz, M. A. (1992) Neurogenicversus vascular mechanisms of sumatriptan and ergot alkaloids inmigraine. Trends Pharmacol. Sci. 13, 307-311).

Migraine therapy is either prophylactic or symptomatic. Prophylacticmedication may be selected for a patient having two to four or moreheadaches per month, if they are severe enough to interfere with dailyactivities. Beta blockers such as propranolol (INDERAL®) are the mostcommonly used. Other medications frequently used include serotoninantagonists such as methysergide maleate (SANSERT®), calcium channelblockers (VERAPAMIL®), amitriptyline (ELAVIL®), and ergotaminepreparations with belladonna alkaloids and phenobarbital. All of thesemedications have significant side effects including sedation, loss ofenergy and drive, dry mouth, constipation, weight gain, andgastrointestinal cramping and distress. For symptomatic treatment,ergotamine with caffeine) (CAFERGOT®) is commonly used. Othermedications employed for treating migraine include isometheptene mucate)(MIDRIN®, non-steroidal anti-inflammatory drugs (NSAID's such asMOTRIN®, NAPROXEN®, etc.), dihydroergotamine and the newer triptans,such as sumatriptan) (IMITREX®, etc. When narcotics, such as FIORINALWITH CODEINE® (butalbital with codeine) are used frequently, additionalhazards, including the considerable potential for rebound headaches andhabituation are encountered.

The administration of serotonin agonists is well established for thetreatment of migraine headache. The serotonin agonists most widely usedare the triptans, including sumatriptan, zolmitriptan, naratriptan,rizatriptan, eletriptan, frovatriptan and almotriptan. These compoundsbind specifically to serotonin 5-HT_(1D/1B) receptors. To a lesserdegree, ergot alkaloids such as ergotamine tartrate (referred to hereinas ergotamine) and dihydroergotamine mesylate (also referred to asdihydroergotamine or DHE) are also used to a variety of disease states,including, but not limited to the treatment of acute migraine.

Ergotamine and DHE have very low rectal, oral, sublingual and intranasalbioavailability (only 2% to 10% of the administered dose reaches thesystemic circulation). These administration routes also result inrelatively slow onset of therapeutic efficacy, ranging from 45 minutesfor intranasal to 2 hours for oral or sublingual delivery. IVadministration has high bioavailability and onset of therapeuticefficacy, usually much less than 30 minutes. However, injections arepainful, cause local inflammation, reduce compliance, and becauseadministration by IV requires costly clinical supervision, it would bevery desirable to administer the ergot alkaloids by pulmonaryinhalation. Pulmonary inhalation of the ergot alkaloids would minimizemetabolism before the drugs can reach the circulation because there israpid transport from the alveolar epithelium into the capillarycirculation and because of the relative absence of mechanisms formetabolism in the lungs. Pulmonary delivery has been demonstrated toresult in up to 92% bioavailability in the case of ergotamine tartrate.Pulmonary inhalation administration would also avoid gastrointestinalintolerance typical of migraine medications and minimize the undesirabletaste experienced with nasal and sublingual administration due to thebitterness of the ergot alkaloids. Pulmonary inhalation would minimizethe reluctance to administer treatment associated with the invasivenessof injection and the cost of clinical supervision. Pulmonary inhalationalso would allow for rapid relief from the migraine symptoms, as itwould deliver the drug to the systemic circulation as fast as an IVbolus, less than 30 minutes, without the invasive nature of injection.

Dihydroergotamine (DHE) was identified as an effective treatment formigraine nearly fifty years ago (Raskin, Neurology 36:995 997 (1986);Silberstein, et al., Headache 30:334 339 (1990); Saadah, Headache 32:1820 (1992); and Winner, Headache 33:471 475 (1993)). Despite numerousreferences describing aerosol delivery of ergotamine tartrate, alsoreferred to as ergotamine, for pulmonary inhalation, there are few, ifany, teachings related to the delivery of DHE via pulmonary inhalation.Delivery of DHE in the same manner as ergotamine tartrate is not easilyaccomplished because DHE is very difficult to stabilize in any of theabove formulations. DHE (D.H.E. 45®-Novartis) has been administered byintramuscular or intravenous (IV) injection for over 50 years (Belgrade,et al., Neurology 39:590 592 (1989); Winner, Headache 33:471 475(1993)). DHE (MIGRANAL®—Novartis) has been administered by nasaladministration for 10 years. DHE is also effective when givensubcutaneously (Klapper, et al., Headache 32:21 23 (1992); Winner, etal., Arch. Neurol. 53:180 184 (1996); and Becker, et al., Headache36:144 148 (1996)). However, its administration has been associated withan undesirable side effect profile: nausea, emesis, chest tightness andrelated cardiovascular effects such as blood pressure instability andarterial constriction, have been reported with its use.

Although effective in the treatment of migraine, DHE administration isoften accompanied by side effects such as nausea, vomiting and chestpain (Winner, et al., Arch. Neurol. 53:180 184 (1996)). Other sideeffects observed from postmarketing experience in patients receivingD.H.E. 45® (dihydroergotamine mesylate) injection, USP, includevasospasm, paraesthesia, hypertension, dizziness, anxiety, dyspnea,headache, flushing, diarrhea, rash, increased sweating, cardiacvalvulopathy, and pleural and retroperitoneal fibrosis seen afterlong-term use of dihydroergotamine. At least one side effect, nausea,occurs more frequently after intravenous administration than afterintramuscular or intranasal administration. When given subcutaneously ata concentration of only 1.5 mM, DHE has been reported to cause nausea innearly 16% of treated patients (Winner, et al., Arch. Neurol. 53: 80 184(1996)). The currently accepted treatment algorithms for injection or IVuse of DHE (see FIGS. 6A-6B) call for the administration of anantiemetic prior to or concurrent with administration of DHE to preventnausea. Patients with known cardiovascular disease are not qualified toreceive DHE treatment.

Notwithstanding these undesirable side effects DHE is still consideredthe “gold standard” for treatment of severe migraine, cluster headache,chronic daily headache. DHE has a longer duration of action thansumatriptan, so headache recurrence rates are lower with its use.(Winner P, et al. A double blind study of subcutaneous dihydroergotamineversus subcutaneous sumatriptan in the treatment of acute migraine. ArchNeurol (1996) 53:180-184.) Thus, there exists a need for procedures todeliver therapeutically effective amounts of DHE in a time-sensitivemanner, without precipitating the side-effects traditionally associatedwith its administration.

SUMMARY OF THE INVENTION

The invention relates to a method for rapid treatment of a disease orcondition in an individual with a compound that (a) binds to one or morefirst receptors, wherein binding of the compound to the first receptorsalleviates the disease or condition, and (b) binds to one or more secondreceptors, wherein binding of the compound to the second receptorscauses a side effect, the method comprising: administering to theindividual an amount of the compound at a rate sufficient to develop acirculating plasma concentration level of the compound such thatcompound acts as an agonist against the first receptor and providesrelief from the disease or condition, wherein the circulating plasmaconcentration level of the compound remains below a level necessary forbinding to the second receptor to cause a side effect.

In one embodiment, the invention relates to a method for rapid treatmentof migraine with DHE, while minimizing side effects, the methodcomprising: dampening the peak plasma concentration (C_(max)) andslightly delaying the peak such as to avoid saturating the dopaminergicand adrenergic receptors, while achieving sufficient binding to theserotonin receptors to alleviate migraine symptoms within a timeframethat permits rapid resolution of migraine symptoms.

In one embodiment, the invention relates to a method for administeringDHE or salts, hydrates, polymorphs, prodrugs, ion pairs and metabolitesthereof, to a patient in need thereof, an amount of DHE sufficient toreduce a migraine symptom within a 2 hour period, without inducingside-effects.

The invention relates to methods for providing an amount of DHE to anindividual sufficient to develop a circulating plasma concentrationlevel of DHE effective for DHE to act as an agonist against a serotoninreceptor related to alleviating a migraine symptoms, while insufficientfor active binding to an adrenergic or dopaminergic receptor related tonausea and other side effects.

In some embodiments, DHE displays reduced (<50%) or absence of (<20%)active binding at dopaminergic receptors such as D₂. In someembodiments, DHE displays absence of (<20%) active binding at 5-HT₃receptors. In some embodiments, In some embodiments, DHE displaysreduced (<60%) or absence of (<20%) active binding at adrenergicreceptors.

In one embodiment, the DHE is administered by any method at a rate suchthat the C_(max) is less than 40,000 pg/ml concentration in thecirculating plasma in humans, and the time following administration whenthe peak plasma concentration is attained (T_(max)) occurs within 30minutes after administration.

In some embodiments, C_(max) of DHE is less than 20,000 pg/mL, or lessthan 15,000 pg/mL, or less than 10,000 pg/mL, or less than 7,500 pg/mLin the circulating plasma. In some embodiments, T_(max) of DHE ispreferably less than 20 minutes, and most preferably 15 minutes in thecirculating plasma.

According to one aspect of the invention the C_(max) of DHE administeredby a method of the invention is at least 5-fold, 10-fold or 15-foldreduced from the C_(max) of DHE administered by direct or slow bolusintravenous delivery.

According to one aspect of the invention the T_(max) of DHE administeredby a method of the invention is at least 1 minute delayed from theT_(max) of DHE administered by direct intravenous delivery, and the AUC(or area of the curve of the concentration of the drug in the systemiccirculation versus time) of the drug delivered by the method of theinvention is within 75% of the comparable IV delivered dose.

According to one aspect of the invention the DHE formulation isadministered to an individual by a breath activated metered doseinhaler, wherein the DHE is administered at a rate such that the peakplasma concentration (C_(max)) is less than 10,000 pg/ml concentrationin the circulating plasma in humans, and the time (T_(max)) followingadministration when the peak plasma concentration is attained, is lessthan 20 minutes after administration, and further wherein the DHEformulation is administered without administering an anti-emetic to theindividual.

According to the methods of the invention, administration of DHE toachieve C_(max) and T_(max) as described above, results in at leastpartial relief from a migraine syndrome including but not limited topain, nausea, phonophobia and photophobia, within 30 minutes andsustained relief for 24 hours, but does not result in drug inducednausea, cardiovascular side effects or other adverse effects.

According to one embodiment, the at least partial relief from a migrainesyndrome is measured by a drop from a IHS score of greater than “0” fora migraine symptom at the time of administration of DHE, to a score of≦1 at 30, 60, 90 or 120 minutes following administration.

According to the methods of the invention, administration results inpeak plasma concentrations of the primary active metabolites, includingbut not limited to 8-hydroxy dihydroergotamine, at less than 40,000pg/ml at C_(max). In some embodiments, C_(max) of the primarymetabolites is preferably less than 1,000 pg/mL, more preferably lessthan 500 pg/mL, and most preferably less than 200 pg/mL in thecirculating plasma. In some embodiments, the T_(max) of the primarymetabolites is preferably less than 90 minutes, and most preferably 60minutes in the circulating plasma.

In one aspect of the invention, the method involves administration tothe systemic circulation of an unit dose of less than 3.0 mg DHE orsalts, hydrates, polymorphs prodrugs, ion pairs and metabolites thereof.In a preferred embodiment, an unit dose of 1.0 mg is administered.

The invention also relates to suitable DHE formulations that achieve thedesired delivery profile when administered to an individual.

According to the methods of the invention a DHE formulation may beadministered by any mode, including but not limited to, intravenous,intra-arterial, intraperitoneal, intrapulmonary, oral, sublingual,buccal, intranasal, oral inhalation, intravesicular, intramuscular,intra-tracheal, subcutaneous, iontophoresis, transdermal, intraocular,intrathecal, transmucosal, and transdermal delivery.

In a preferred mode, the method of administration is by pulmonaryinhalation using aerosols, dry powder inhalers, nebulizers, vaporizers,pressurized metered dose inhalers (pMDIs) and the like. In a morepreferred embodiment a pMDI such as a breath activated metered doseinhaler (for example, TEMPO™ Inhaler from Map Pharmaceuticals, MountainView, Calif.) is used to administer DHE.

The invention also relates to kits comprising DHE formulations andinstructions for use thereof. In a preferred embodiment, an inhalerdevice is included. In one embodiment of this kit, the inhaler device isloaded with a DHE formulation. In another embodiment the kit comprisesone or more unit doses of the DHE formulation. In one embodiment, theinhaler device is a pMDI such as a breath activated metered dose inhaler(TEMPO™ Inhaler).

The invention further relates to an inhaler device comprising one ormore unit doses of a DHE formulation wherein each unit dose isadministered at a rate such that the peak plasma concentration (C_(max))is less than 10,000 pg/ml concentration in the circulating plasma inhumans, and the time (T_(max) ) following administration when the peakplasma concentration is attained, is less than 30 minutes afteradministration.

The present invention and other objects, features, and advantages of thepresent invention will become further apparent in the following DetailedDescription of the Invention and the accompanying Figures andembodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows percentage of subjects obtaining relief from pain with DHEversus placebo.

FIG. 2 shows pharmacokinetic profiles for achieving pain relief withminimal side effects.

FIG. 3 shows radioligand receptor binding profile for serotonergicreceptor subtypes based on dose and administration route. Less than 20%was classed as inactive binding. “(h)” represents cloned human receptorsubtypes.

FIG. 4 shows radioligand receptor binding profile for adrenergic anddopaminergic receptor subtypes based on dose and administration route.Less than 20% was classed as inactive binding. “(h)” represents clonedhuman receptor subtypes and “NS” indicates non-specific binding.

FIG. 5 shows selective agonism at 5-HT_(1B) and 5-HT_(2B) receptors atvarious concentrations of DHE.

FIG. 6A and FIG. 6B show currently accepted treatment algorithms forinjection or IV administration of DHE.

FIG. 7 shows geometric mean 8′OH-DHE concentrations over time followingadministration of DHE by inhalation and intravenous (IV) routes.

DETAILED DESCRIPTION OF THE INVENTION

Use of the term Dihydroergotamine (DHE) according to the methods ofinvention comprises DHE or salts, hydrates, polymorphs prodrugs, ionpairs and metabolites thereof.

The invention relates to a method for administering DHE or salts,hydrates, polymorphs prodrugs, ion pairs and metabolites thereof, to apatient in need thereof, an amount of DHE sufficient to reduce amigraine symptom within a specified period hour period, without inducingside-effects.

To reduce a migraine symptom within a specified period hour period mayinvolve providing partial relief from at least one migraine syndromewhich includes but is not limited to pain, nausea, phonophobia andphotophobia, within a period 30, 60, 90, 120 or 180 minutes. Reductionof a migraine symptom further may comprise providing sustained relieffor 6, 12, 18, 24 or 36 hours.

Relief from any of the migraine symptoms is measured by a drop from aIHS score of greater than “0” (score of >1 for pain) at the time ofadministration of DHE, to a score of ≦1 at 30, 60, 90, 120 or 180minutes following administration. However, freedom from pain (or othersevere symptoms) require a reduction in grading of that symptom from aninitial >0 result (score of >1 for pain) to 0 at the time point inquestion.

To reduce a migraine symptom without inducing side-effects may involveadministration of therapeutically effective amounts of DHE not resultingin drug induced nausea, emesis, chest tightness and relatedcardiovascular effects such as blood pressure instability and arterialconstriction, or any other adverse effects known to be associated withtreatment of migraine with DHE.

The invention relates to methods for providing an amount of DHE to anindividual sufficient to develop a circulating plasma concentrationlevel of DHE effective for DHE to act as an agonist against a serotoninreceptor related to alleviating a migraine symptoms, wherein the C_(max)is attained within a time period (T_(max)) sufficient for providingpartial relief from at least one migraine syndrome including but notlimited to pain, nausea, phonophobia and photophobia, within a period30, 60, 90, 120 or 180 minutes, or providing sustained relief for 6, 12,18, 24 or 36 hours.

Further, the C_(max) attained within a time period (T_(max)) accordingto administration methods of this invention are insufficient for activebinding of DHE to an adrenergic or dopaminergic receptor and causingnausea and other side effects.

When binding of DHE to an adrenergic or dopaminergic receptor isinsufficient for causing nausea and other side effects, DHE displaysreduced (less than 50%) or absence of (20% or less) binding atdopaminergic receptors such as D₂; and DHE displays reduced (less than60%) or absence of (20% or less) binding at adrenergic receptors.

According to the invention, DHE is administered by any method at a ratesuch that the C_(max) is less than 5,000, 10,000, 20,000, 30,000,40,000, 50,000, or 60,000 pg/ml concentration in the circulating plasmain humans, and the time following administration when the peak plasmaconcentration is attained (T_(max)) occurs within 10, 15, 20, 30, 45 or60 minutes after administration.

According to the methods of the invention, administration results inpeak plasma concentrations of the primary active metabolites, includingbut not limited to 8-hydroxy dihydroergotamine, at less than 5,000,10,000, 20,000, 30,000, 40,000, 50,000, 60,000, 100,000 or 200,000 pg/mlat C_(max). The T_(max) of the primary metabolites is less than 30, 45,60, 90, or 120 minutes after administration.

According to one aspect of the invention the C_(max) of DHE administeredby a method of the invention is at least 5-fold, 10-fold, or 15-foldreduced from the C_(max) of DHE administered by direct intravenousdelivery.

According to one aspect of the invention the T_(max) of DHE administeredby a method of the invention is at least 1, 2, 5, 10 or 15 minutesdelayed from the T_(max) of DHE administered by direct intravenousdelivery, and the AUC (or area the curve of the concentration of thedrug in the systemic circulation versus time) of the drug delivered bythe method of the invention is within 75% of the comparable IV delivereddose.

In one aspect of the invention, the method involves administration of anunit dose comprising about 0.5, 1.0, 2.0, 3.0 or 5.0 mg DHE or salts,hydrates, polymorphs prodrugs, ion pairs and metabolites thereof.

The invention relates to packaged vials, canisters, ampoules, packs, orpatches comprising one or more unit doses of DHE. Unit doses may beformulated and packaged in a manner suitable for administration byintravenous, intra-arterial, intraperitoneal, intrapulmonary, oral,sublingual, buccal, intranasal, oral inhalation, intravesicular,intramuscular, intra-tracheal, subcutaneous, iontophoretic, transdermaldelivery. In preferred embodiments, the doses of DHE are packaged in amanner suitable for intravenous delivery or pulmonary inhalation.

The invention also relates to suitable solid, liquid or aerosolformulations of DHE that, when administered to a mammal underappropriate conditions, achieve the desired delivery profile defined byAUC, C_(max) and T_(max) values listed above.

According to the methods of the invention a DHE formulation may beadministered by any mode necessary to achieve the desired deliveryprofile defined by C_(max) and T_(max) values listed above, includingbut not limited to, by intravenous, intra-arterial, intraperitoneal,intrapulmonary, oral, sublingual, buccal, intranasal, oral inhalation,intravesicular, intramuscular, intra-tracheal, subcutaneous,iontophoretic, transdermal administration.

Typically, the DHE formulation will be distributed, either to clinics,to physicians or to patients, in an administration kit, and theinvention provides such a migraine treatment kit. Such kits comprise oneor more of an administration device (e.g., syringes and needles,inhalators, etc) and a plurality of unit dosages or a reservoir or cacheconfigured to deliver multiple unit doses of the composition asdescribed above. In one embodiment, the administration device is loadedwith a DHE formulation The kit can additionally comprise a carrier ordiluent, a case, and instructions for employing the appropriateadministration device. In some embodiments, an inhaler device isincluded. In one embodiment of this kit, the inhaler device is loadedwith a reservoir containing the DHE formulation. In another embodimentthe kit comprises one or more unit doses of the DHE formulation. In oneembodiment, the inhaler device is a pMDI such as a breath activatedmetered dose inhaler (TEMPO™ Inhaler).

Dihydroergotamine (DHE) for Treatment of Migraine

Dihydroergotamine (DHE) is a semi-synthetic ergot alkaloid, which hasbeen used in the treatment of migraine since 1946. Due to structuralsimilarities with physiological molecules, DHE has wide rangingpharmacology (Table 1), mediated by effects on biogenic aminereceptors—specifically serotonin (5-HT) subtypes, adrenergic (α and β)subtypes and dopaminergic (D) subtypes).

Dihydroergotamine is used extensively to treat cluster migraine,pediatric migraine, status migrainosus and chronic daily headache,formerly referred to as “transformed” migraine. DHE is currentlyadministered orally and intranasally (MIGRANAL®-Novartis, U.S. Pat. No.5,942,251, EP0865789A3, and BE1006872A). However, DHE is most oftenadministered by intramuscular/subcutaneous injection or by intravenousinjection (D.H.E. 45®-Novartis) in a clinical setting. (Raskin N H,Neurol Clin. 1990 November; 8(4):857-65.)

Dihydroergotamine binds with high affinity to 5-HT_(1Dα)and5-HT_(1Dβ)receptors. It also binds with high affinity to serotonin5-HT_(2A), and 5-HT_(2C) receptors, noradrenaline α_(2A), α_(2B) and α₁receptors, and dopamine D_(2L) and D₃ receptors.

The therapeutic activity of dihydroergotamine in migraine is generallyattributed to the agonist effect at 5-HT_(1D) receptors. Two currenttheories have been proposed to explain the efficacy of 5-HT_(1D)receptor agonists in migraine. One theory suggests that activation of5-HT_(1D) receptors located on intracranial blood vessels, includingthose on arteriovenous anastomoses, leads to vasoconstriction, whichcorrelates with the relief of migraine headache. The alternativehypothesis suggests that activation of 5-HT_(1D) receptors on sensorynerve endings of the trigeminal system results in the inhibition ofpro-inflammatory neuropeptide release. In addition, dihydroergotaminepossesses oxytocic properties.

The ergot alkaloids are less selective than the triptans when binding to5-HT_(1D), 5-HT_(1A), 5-HT_(2A), 5-HT_(2C), noradrenaline□ α_(2A),α_(2B), and α, dopamine D_(2L) and D₃ receptors. In acute migrainetherapy, DHE is thought to mediate its effects through 5-HT_(1B)receptors (constriction of intracranial extra-cerebral blood vessels)and 5-HT_(1D) receptors (inhibition of trigeminal neurotransmission).

DHE is known to bind specifically to receptors as shown in Table 1.Table 1 shows affinities of DHE (measured as IC₅₀) for specific biogenicamine receptors. Potent activity at 5-HT_(1B) and 5-HT_(1D) receptorsand wide ranging receptor-binding activity is observed for DHE.(Silberstein, S. D., McCrory, D. C. Ergotamine and dihydroergotamine:history, pharmacology, and efficacy. Headache (2003) 43:144-166.)

The chemical structure of DHE is shown below:

Formulations and Dosage Forms

A number of studies have been conducted in adults to demonstrate theefficacy and safety of intravenous DHE. The current method ofadministering intravenous DHE by using repeated intravenous doses of DHEto treat severe migraines was introduced by Raskin. (Raskin N H.Repetitive intravenous dihydroergotamine as therapy for intractablemigraine. Neurology 1986; 36: 995-997). References to “directintravenous delivery” in the specification is understood to refer todirect IV administration of DHE according to the procedure set forth inRaskin (Neurology 36: 995-997 (1986)).

Recently, formulations of DHE by itself and in combination withnonsteroidal analgesics have been developed for intramuscularautoinjectors (US 20030040537, U.S. Pat. No.6,077,539, WO005781A3,EP1165044A2, CN1347313T, and AU0038825A5). DHE in combination withpotent analgesics had also been formulated for treatment by intranasaladministration (U.S. Pat. No. 5,756,483, EP0689438A1, AU6428894A1, andWO9422445A3). Spray or aerosol formulations have also been developed forthe sublingual administration of DHE (US20030017994). Ergotaminetartrate has been administered by injection, rectally with suppositoriesand via inhalation with metered dose inhaler (MEDIHALER-ERGOTAMINE®; 3MHealth Care, Northridge, Calif.), but is most commonly administeredorally or sublingually.

There are numerous recent citations of ergotamine tartrate formulationsfor administration via inhalation (U.S. Pat. No. 6,488,648, U.S. Pat.No. 6,451,287, U.S. Pat. No. 6,395,300, U.S. Pat. No. 6,395,299, U.S.Pat. No. 6,390,291, U.S. Pat. No. 6,315,122, U.S. Pat. No. 6,179,118,U.S. Pat. No. 6,119,853, U.S. Pat. No. 6,406,681) and specifically inpropellant based metered dose inhaler (MDI) formulations (U.S. Pat. No.5,720,940, U.S. Pat. No. 5,683,677, U.S. Pat. No. 5,776,434, U.S. Pat.No. 5,776,573, U.S. Pat. No. 6,153,173, U.S. Pat. No. 6,309,624, U.S.Pat. No. 6,013,245, U.S. Pat. No. 6,200,549, U.S. Pat. No. 6,221,339,U.S. Pat. No. 6,236,747, U.S. Pat. No. 6,251,368, U.S. Pat. No.6,306,369, U.S. Pat. No. 6,253,762, U.S. Pat. No. 6,149,892, U.S. Pat.No. 6,284,287, U.S. Pat. No. 5,744,123, U.S. Pat. No. 5,916,540, U.S.Pat. No. 5,955,439, U.S. Pat. No. 5,992,306, U.S. Pat. No. 5,849,265,U.S. Pat. No. 5,833,950, U.S. Pat. No. 5,817,293, U.S. Pat. No.6,143,277, U.S. Pat. No. 6,131,566, U.S. Pat. No. 5,736,124, U.S. Pat.No. 5,696,744). In the late 1980s 3M developed, received approval forand marketed a pulmonary inhalation formulation of an ergotaminetartrate (MEDIHALER-ERGOTAMINE®). It was removed from the market in the1990s due to difficulties with inconsistent formulation.

Powders for inhalation in dry powder inhalation devices using ergotaminetartrate have also been described (U.S. Pat. No. 6,200,293, U.S. Pat.No. 6,120,613, U.S. Pat. No. 6,183,782, U.S. Pat. No. 6,129,905, U.S.Pat. No. 6,309,623, U.S. Pat. No. 5,619,984, U.S. Pat. No. 4,524,769,U.S. Pat. No. 5,740,793, U.S. Pat. No. 5,875,766, U.S. Pat. No.6,098,619, U.S. Pat. No. 6,012,454, U.S. Pat. No. 5,972,388, U.S. Pat.No. 5,922,306). An aqueous aerosol ergotamine tartrate formulation forpulmonary administration has also been described (U.S. Pat. No.5,813,597).

The invention is directed to a pharmaceutical composition in unit doseform containing DHE in an amount such that one or more unit doses areeffective in the symptomatic treatment of migraine headache whenadministered to a patient. The composition may contain excipients. Inorder to retard the rate of oxidative degradation of the composition,one or more antioxidants may be added. Any salt of DHE may be used butthe mesylate salt is preferred. In all cases, formulations may beprepared using methods that are standard in the art (see, e.g.,Remington: The Science and Practice of Pharmacy, 21st ed., LippincottWilliams & Wilkins (2005)). In general, patients receive a total dosageof between 0.1 and 10.0 mg, preferably 0.5 to 5.0 mg, or more preferably1.0-2.0 mg per migraine attack. The dose of the DHE formulationadministered to an individual (such as human) will vary with theparticular composition and the method of administration, such as toachieve the necessary biogenic amine receptor binding profile requiredfor treating migraine without triggering side effects or adverseeffects.

The term “unit dosage form” refers to a physically discrete unitsuitable as unitary dosages for an individual, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical carrier, diluent, or excipient. These unit dosage formscan be stored in a suitable packaging in single or multiple unit dosagesand may also be further sterilized and sealed.

Also provided are articles of manufacture comprising the compositionsdescribed herein in suitable packaging. Suitable packaging forcompositions described herein are known in the art, and include, forexample, vials (such as sealed vials), canisters with metering valves,vessels, ampoules, bottles, jars, flexible packaging (e.g., sealed Mylaror plastic bags), and the like. These articles of manufacture mayfurther be sterilized and/or sealed.

The compositions may further comprise additional ingredients, forexample preservatives, buffers, tonicity agents, antioxidants andstabilizers, nonionic wetting or clarifying agents, viscosity-increasingagents, absorption enhancing agents, and the like.

Suitable absorption enhancement agents include N-acetylcysteine,polyethylene glycols, caffeine, cyclodextrin, glycerol, alkylsaccharides, lipids, lecithin, dimethylsulfoxide, and the like.

Suitable preservatives for use in a solution include polyquaternium-1,benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propylparaben, phenylethyl alcohol, disodium edetate, sorbic acid,benzethonium chloride, and the like. Typically (but not necessarily)such preservatives are employed at a level of from 0.001% to 1.0% byweight.

Suitable buffers include boric acid, sodium and potassium bicarbonate,sodium and potassium borates, sodium and potassium carbonate, sodiumacetate, sodium biphosphate and the like, in amounts sufficient tomaintain the pH at between about pH 6 and pH 8, and preferably, betweenabout pH 7 and pH 7.5.

Suitable tonicity agents are dextran 40, dextran 70, dextrose, glycerin,potassium chloride, propylene glycol, sodium chloride, and the like,such that the sodium chloride equivalent of the ophthalmic solution isin the range 0.9 plus or minus 0.2%.

Suitable antioxidants and stabilizers include sodium bisulfite, sodiummetabisulfite, sodium thiosulfite, thiourea, caffeine, cromoglycatesalts, cyclodextrins and the like. Suitable wetting and clarifyingagents include polysorbate 80, polysorbate 20, poloxamer 282 andtyloxapol. Suitable viscosity-increasing agents include dextran 40,dextran 70, gelatin, glycerin, hydroxyethylcellulose,hydroxmethylpropylcellulose, lanolin, methylcellulose, petrolatum,polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone,carboxymethylcellulose and the like.

Modes of Administration

The compositions described herein can be administered to an individual(such as human) via various routes, including, for example, intravenous,intra-arterial, intraperitoneal, intrapulmonary, oral, inhalation,intravesicular, intramuscular, intra-tracheal, subcutaneous,intraocular, intrathecal, transmucosal, and transdermal. In oneembodiment of the invention, nanoparticles (including protein orcarbohydrate nanoparticles, co-formulated with drug) of the inventivecompounds can be administered by any acceptable route including, but notlimited to, orally, intramuscularly, transdermally, intravenously,through an inhaler or other air borne delivery systems and the like.

When preparing the composition for injection, particularly forintravenous delivery, the continuous phase preferably comprises anaqueous solution of tonicity modifiers, buffered to a pH range of about4 to about 8.5. The pH may also be below 7 or below 6. In someembodiments, the pH of the composition is no less than about 6,including for example no less than about any of 6.5, 7, or 8 (such asabout 7.5 or 8).

In a preferred embodiment the DHE is delivered using inhalation therapy.Many preclinical and clinical studies with inhaled compounds havedemonstrated that efficacy can be achieved both within the lungs andsystemically. Moreover, there are many advantages associated withpulmonary delivery including rapid onset, the convenience of patientself-administration, the potential for reduced drug side-effects, easeof delivery by inhalation, the elimination of needles, and the like.

Inhalation aerosols from dry powder inhalers, nebulizers, vaporizers andpressurized metered dose inhalers typically include excipients orsolvents to increase stability or deliverability of these drugs in anaerosol form. Additionally, the particle size of the drug aerosols maybe controlled to provide the uptake characteristics consistent with themethods of the invention. Typically, particle sizes are controlled todesirable sizes known by those skilled in the art. For example, whenusing dry powder inhalers (DPI's), the drug particles are generated fromthe bulk drug by attrition processes such as grinding, micronizing,milling, or by multiphase precipitation processes such as spray drying,solution precipitation, supercritical extraction/precipitation orlyophilization to yield powders that can be dispersed in the propellantto obtain an acceptable particle size for delivery to the lungs. As drypowder formulations are prone to aggregation and low flowability whichcan result in diminished efficiency, scrupulous attention is requiredduring milling, blending, powder flow, filling and even administrationto ensure that the dry powder aerosols are reliably delivered and havethe proper particle size distribution for delivery to the lungs.

Nebulizers generate an aerosol from a liquid, some by breakup of aliquid jet and some by ultrasonic vibration of the liquid with orwithout a nozzle. Liquid formulations are prepared and stored underaseptic or sterile conditions since they can harbor microorganisms. Theuse of preservatives and unit dose packaging is contemplated.Additionally solvents, detergents and other agents are used to stabilizethe drug formulation.

Pressurized metered dose inhalers, or pMDIs, are an additional class ofaerosol dispensing devices. pMDIs package the compound in a canisterunder pressure with a solvent and propellant mixture, usuallychlorofluorocarbons (CFCs,), or hydroflouroalkanes (HFAs). Upon beingdispensed a jet of the mixture is ejected through a valve and nozzle andthe propellant “flashes off” leaving an aerosol of the compound. Due tothe high speed ejection of the aerosol from the nozzle, some of the drugmay impact ballistically on the tongue, mouth and throat and never reachthe lung.

While aerosol delivery of ergotamine tartrate for pulmonary inhalationis widely known, delivery of DHE via pulmonary inhalation has been usedrarely, as DHE is very difficult to stabilize in formulations suitablefor pulmonary delivery. To maintain potency and activity the DHE must beformulated in a solution, powder or suspension that can be stabilizedwithout excipients or with excipients that are not toxic to the lungs.Since DHE is extremely sensitive and will degrade on exposure to light,oxygen, heat and in the presence of many chemical compounds commonlyused in medicinal formulations, stabilization is not easily achieved.The current formulations for delivery of DHE by aqueous nasal sprays orby injection require chelating or complexing agents, such as dextran orcyclodextrins, to stabilize the DHE in solution. To preserve the DHEsolution from degradation it is sealed in difficult-to-use dark-glassvials that must be opened with a complicated opener and transferred toinjector or spray applicator immediately prior to use. Only recentlystable formulations for pulmonary delivery of DHE have been described inU.S. application Ser. No. 10/572,012 and WO2005/025506A2.

WO2005/025506A2 describes suitable, stable formulations ofdihydroergotamine, or pharmaceutically acceptable salts thereof, toadminister dry powders and propellant suspensions via pulmonary aerosolinhalation or nasal spray inhalation. In one embodiment, DHE is used asthe mesylate salt. The DHE powder is generated using supercritical fluidprocesses which offer significant advantages in the production of DHEparticles for inhalation delivery and produce respirable particles ofthe desired size in a single step. The disclosures of U.S. applicationSer. No. 10/572,012 and WO2005/025506A2 are incorporated herein byreference in their entirety.

In a preferred embodiment, the inhaled dosing is carried out with abreath actuated inhaler such as the Tempo™ Inhaler (Map Pharmaceuticals,Inc., Mountain View, Calif.). The Tempo™ Inhaler is a pressurizedmetered-dose inhaler (pMDI) which addresses limitations of standard pMDIinhalers: inconsistent dosing and drug delivery inefficiency. The TempoInhaler provides breath actuation, enhancing patient compliance, andefficient, reliable dose-to-dose consistency that is independent of theinhalation flow rate. It achieves these advantages by combiningproprietary features such as the breath synchronized trigger and theflow control chamber and dose counter/lockout in a small, easy to usedevice. These advanced aerodynamic control elements are driven only bythe patient's breath, avoiding expensive, power consuming electronics,resulting in an affordable, reliable and disposable platform.

Measuring Efficiency of DHE Administration

The current invention teaches a method of administration of DHE thatminimizes or eliminates side effects while at the same time achieving adosing profile sufficient to provide effective and rapid relief from thefour primary symptoms of migraine syndrome: pain, nausea, phonophobiaand photophobia. In clinical trials conducted by the inventors, anunanticipated phenomenon was observed. When DHE was administered in theaforementioned manner, a very high “spike” in peak plasma concentrationwas unexpectedly avoided, the side effects of nausea, chest tightness orpain, blood pressure excursions, emesis could be minimized or completelyeliminated while still achieving rapid relief from the migrainesymptoms.

Efficacy of a migraine therapy regimen can be evaluated based on primaryand secondary endpoints. Primary efficacy endpoint may be a pain-freeresponse rate at about 2 hours post-dose. Secondary efficacy endpointsexamine 3 areas of interest: pain-free response at time points earlierthan 2 hours post-dose; non-progression of headache; and impact onnormal activities.

All four migraine symptoms—pain, nausea, phonophobia and photophobia—arescored at each time point on a four point scale developed by theInternational Headache Society (IHS; International Headache SocietyCommittee on Clinical Trials in Migraine. Guidelines for controlledclinical trials of drugs in migraine, 1st ed. Cephalalgia 1991;11:1-12):

0=none

1=mild symptom, not interfering with normal daily activities

2=moderate symptom, causing some restriction to normal activities

3=severe, leading to inability to perform normal daily activities

Headache pain intensity is measured on the 4-point severity scale (0=nopain, 1=mild, 2=moderate, 3=severe). The average time to headacheimprovement (one point below the original intensity), to mild headache,and to no headache is measured. An effective migraine therapy wouldreduce a headache symptom to mild or non by 1.5 to 2 hours.

Relief from any of the four symptoms require a drop from a score of >0at time of report of onset of migraine attack (score of >1 for pain), toa score of ≦1 at the time point in question. However, freedom from pain(or other symptom) require a reduction in grading of that symptom froman initial >0 result (score of >1 for pain) to 0 at the timepoint inquestion.

Functional disability (ability to perform usual daily activities) ismeasured with a 4 point scale:

0=not at all impaired

1=slightly impaired

2=moderately impaired

3=severely or completely impaired

There is a further question (How well did your Study Medication work?)at certain timepoints asking subjects to evaluate the “globaleffectiveness” of their study medication using a 7 point categoricalscale:

0=very much better

1=much better

2=a little better

3=no change

4=a little worse

5=much worse

6=very much worse

Mechanisms of Action

Investigation of receptor binding at the C_(max) concentrationsdescribed in detail in Examples 2 and 3, provided a rationale for thedifferences observed in the adverse effect profile. Without being boundby theory, it is hypothesized that a method for treating migraine withDHE without triggering side effects can be achieved by controlling theC_(max) concentration to minimize binding to dopaminergic and adrenergicreceptors and thus avoiding side effects, while achieving sufficientserotonin receptor binding to be effective in treating migrainesymptoms.

Clinical data (Table 2) show that inhaled dihydroergotamine reducesincidence of nausea compared to intravenous administration (8% vs. 63%respectively). 5-HT₃ receptors are known to be implicated in nausea.Antagonists at these receptors, such as ondansetron and granisetronprevent chemotherapy-induced nausea and vomiting. However, a potentialagonist role of DHE at 5-HT₃ receptors can be ruled out by inactivebinding (<20%) for all DHE delivery routes investigated (FIG. 3).Subsequent functional assays also confirmed lack of agonist orantagonist activity at 5-HT₃ receptors.

The likely adverse effect profile of DHE is secondary to agonistactivity at 5-HT_(1A), 5-HT_(2A), and dopamine D₂ receptors.(Silberstein, S. D., McCrory, D. C. Ergotamine and dihydroergotamine:history, pharmacology, and efficacy. Headache (2003) 43:144-166.) Thesimilar levels of 5-HT_(1A) receptor binding for all doses andadministration routes rules out this receptor as the cause for thedifferential adverse effect profile, in particular for dizziness.Indeed, 5-HT_(1A) receptors are believed to play a role in DHE-mediatedmigraine prophylaxis. (Hanoun, N., et al. Dihydroergotamine and itsmetabolite, 8-hydroxy-dihydroergotamine, as 5-HT1A receptor agonists inthe rat brain. British Journal of Pharmacology 2003; 139:424-434.)

DHE has excitatory actions at vascular a-adrenergic receptors and haveagonist activity at constrictor 5-HT_(2A) receptors. These actionsunderlie peripheral vasoconstrictor effects, in particular on coronaryartery smooth muscle. As such, DHE and related ergot compounds arecontraindicated in coronary and peripheral vascular disease. It isnotable however that C_(max) binding activity was lower for the higherinhaled (14%) vs. intravenous dosing (83%) at 5-HT_(2A) receptors. Theeffect of other serotonergic subtypes and adrenergic types on theadverse effect profile is not certain. However, binding at C_(max)following intravenous administration yields significantly higher binding(FIGS. 3-5) vs. inhaled C_(max,) which may play a role in nausea, inparticular for adrenergic blockade.

Both neuronal and vascular mechanisms have been proposed as the basis ofactions of 5-HT in migraine. The vasodilatory theory of migrainesuggests that extracranial arterial dilation during an attack is relatedto migraine pain. In the neurogenic dural inflammation theory ofmigraine, inflammation of the dural membrane surrounding the brain isdue to release of neuropeptides from primary sensory nerve terminals.Substance P, calcitonin gene-related peptide and NO all play a role inthe dural inflammatory cascade. NO is suspected to play a key role inmigraine since NO donors cause a dose-dependent headache with severalmigrainous characteristics. A cause of migraine could be increasedamounts and/or affinity of an enzyme in the NO-triggered cascade ofreactions (Olesen et al., Trends Pharmacol. Sci. 1994; 15:149-153).

It has been shown that 5-HT_(2B) receptors stimulate the NO productionin cell lines (Manivet P., et al., PDZ-dependent activation ofnitric-oxide synthases by the serotonin 2B receptor. J. Biol. Chem.2000; 275:9324-9331) and relaxation of the pig cerebral artery (Schmucket al., Eur. J. Neurosci. 1996; 8:959-967). Thus, 5-HT_(2B) receptorslocated on endothelial cells of meningeal blood vessels have beenproposed to trigger migraine headache through the formation of NO. Thelong half-life of DHE may account for the low rate of headacherecurrence at least partially through permanent inhibition of vascular5-HT_(2B)-dependent second messengers (NO) via its major activemetabolite 8′-OH-DHE. (Schaerlinger B., et al., British Journal ofPharmacology (2003) 140, 277-284.)

D2 receptor antagonists, i.e. metoclopramide and domperidone, areeffective anti-nausea therapies. DHE at IV dose C_(max) levels exhibits50% receptor binding in D2 assays (FIG. 5) and therefore may result inthe clinically reported nausea and dizziness, mediated through agonistactivity. Conversely, no binding affinity was reported after inhaleddosing. In addition to data reported here, DHE also has minimal bindingactivity at muscarinic (M) receptors, and thus rules out chemoreceptortrigger zone M receptor-mediated nausea. (McCarthy, B. G., Peroutka, S.J., Comparative neuropharmacology of dihydroergotamine and sumatriptan(GR 43175). Headache 1989; 29:420-422.)

The receptor-binding studies described in Examples 2 and 3 may explainthe unexpected results from the novel method of treating migrainerapidly with DHE, while minimizing side effects. The method dampens thepeak plasma concentration (C_(max)) and slightly delays the peak so asto avoid saturating the dopaminergic and adrenergic receptors, whileachieving sufficient binding to the serotonin receptors to have thedesired therapeutic effect of treating migraine.

EXAMPLES

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following examples are illustrative only, andnot limiting of the remainder of the disclosure in any way whatsoever.

Example 1

Pharmacokinetic Profile of DHE Required to Achieve Pain Relief

FIG. 1 shows the rapid pain relief (within 10 minutes) achieved byadministering DHE by a method that achieves the two lower peak plasmaconcentration profiles shown in FIG. 2.

FIG. 2 shows DHE plasma profiles for 1 mg IV-administered DHE, comparedto 6 inhalations (1.22 mg inhaled/fine particle dose), 4 inhalations(0.88 mg inhaled/fine particle dose) and 2 inhalations (0.44 mginhaled/fine particle dose) of DHE respectively. A large plasma spikewas observed following IV DHE administration, but not with inhaleddelivery of DHE. This plasma spike difference (of at least “10” fold)was hypothesized to be associated with the reduced side effect profile,despite smaller differences in AUC between 1 mg IV and 0.88 mg inhaledDHE.

FIG. 7 shows the plasma profile of the primary metabolite of DHE, 8′-OHDihydroergotamine, following intravenous and inhalation delivery of DHE.A larger plasma spike in 8′-OH Dihydroergotamine was observed followingIV DHE administration, but not with inhaled delivery of DHE. This plasmaspike difference also is hypothesized to be associated with the reducedside effect profile. The inhalable administration results in a peakplasma concentration of 8-hydroxy-dihydroergotamine of less than 1,000pg/ml, preferably less than 500 pg/mL, more preferably less than 200pg/mL at C_(max) in the circulating plasma. The inhalable administrationalso results in the T_(max) of the primary metabolites (e.g., 8′-OHDihydroergotamine) to be less than 90 minutes in the circulating plasma.

The inventors have discovered that these slightly delayed, lower peakpharmacokinetic profiles are associated with minimized side effects. Theside effects elicited by these administration profiles are shown in theTable 2. The two lower curves, 0.88 mg and 0.44 mg DHE in FIG. 2,achieved therapeutic efficacy within 30 minutes, but elicited only minorside effects with the 0.88 mg dose, and no side effects were observedwith the 0.44 mg dose. The highest curve, 1.0 mg IV DHE—the typicaltherapeutic regimen practiced in clinics today-—resulted in significantside effects including nausea and emesis. The observed lower C_(max) orpeak plasma concentration difference which was approximately 10 timeslower than IV, was theorized to be associated with the observeddifferential side effect profile, while the smaller differences in AUC,differences of only “1.2” fold, between 1 mg IV and 0.88 mg inhaledenabled therapeutic efficacy. The delivery profiles shown in FIG. 2 wereachieved in this instance by inhalation administration, but could alsobe achieved by infusion pump, nasal, or iontophoretic transdermal orother routes or administration, that were tailored to give a similarslight delay in reaching peak plasma concentrations and a similardamping of peak concentrations, while achieving similar AUCs.

TABLE 2 Side effects associated with the pharmacokinetic profiles inFIG. 2 1 mg DHE IV, 0.88 mg DHE Inhaled, n = 16 (%) n = 12 (%) NervousSystem Dizziness 7 (44) 7r 1 (8) Paresthesia 5 (31) 5r 0Gastrointestinal System Nausea 10 (63) 10r 1 (8) Vomiting 2 (13) 2r 0General disorders Feeling hot 3 (19) 3r 0 r = considered by investigatorrelated to study drug

Example 2 Receptor Binding at the C_(max) Concentrations

A differential adverse effect profile was reported in a clinical studycomparing 1 mg IV-administered DHE with inhaled DHE (Table 2). A greaterincidence of adverse effects were apparent following IV dosing. Toinvestigate pharmacologically-mediated adverse effect differencesbetween (1) intravenous and (2) inhaled Dihydroergotamine Mesylate(DHE), biogenic amine receptor binding (serotonin (5-HT), adrenergic,dopaminergic) of dihydroergotamine mesylate in vitro was determined,based on concentrations corresponding to the C_(max) levels reportedfollowing inhaled and intravenous (IV) dosing in a clinical study.

To investigate the unexpected result that the lower spikes of DHE mayhave resulted in a different receptor binding profile thus achievingefficacy, but avoiding side effects, a clinical investigation ofreceptor binding at the C_(max) concentrations were undertaken.

Peak Plasma DHE concentrations (C_(max)) were determined from plasmasamples (LC-MS/MS) following intravenous administration (1 mg) byinfusion over 3 minutes, and from plasma samples (LC-MS/MS) followinginhaled dosing (0.88 mg and 0.44 mg doses), where doses were given bymultiple actuations from an inhaler over a period of 2-4 minutes. Theinhaled doses represent the expected systemic delivered dose and wereestimated from the fine particle dose delivered ex-actuator. Theobserved C_(max) data is presented in FIG. 2 for DHE. A similar approachwas also taken with the primary metabolite, 8′-OH-DHE.

Table 3 presents in vitro concentrations equivalent to C_(max). Theseconcentrations were selected for receptor-binding investigations forboth DHE and 8′-OH-DHE.

TABLE 3 Concentrations equivalent to peak plasma concentrationsinvestigated for receptor binding. Dihydroergotamine 8′-OHDihydroergotamine Dose level Mesylate (pg/mL) (pg/mL)   1 mg IV 53,215378 0.88 mg inhaled 4,287 149 0.44 mg inhaled 1,345 58

Example 3 Serotonin, Adrenergic and Dopaminergic Receptor Binding by DHEat Concentrations Equivalent to Peak Plasma Concentrations

Radioligand receptor binding assays clearly show that DHE exhibits wideranging pharmacology at multiple receptor sites. (FIGS. 3-5.) For themajority of receptors, DHE achieves significant binding atconcentrations equivalent to the IV C_(max) whereas inhaled binding ateach dose yields a different profile. In most instances, binding isreduced when non-IV methods are used to administer.

The anti-migraine efficacy of DHE is due to agonist activity at5-HT_(1B) and 5-HT_(1D) receptors. FIG. 3 shows receptor binding data atvarious serotonergic receptor subtypes, indicating greater response atseveral subtypes for intravenous administration at C_(max). The notation“(h)” represents cloned human receptor subtypes. Similar trends wereobserved for adrenergic and dopaminergic subtypes. Binding at thesereceptors is demonstrated with 100% binding at 5-HT_(1B) following both1 mg intravenous and 0.88 mg inhaled dosing. (FIG. 3.) Followinginhalation, however, apparent binding at 5-HT_(1D) receptors is lowerthan IV. The long duration of DHE in circulation beyond C_(max) likelyis due to biphasic elimination. (Wyss, P. A., Rosenthaler, J., Nuesch,E., Aellig, W. H. Pharmacokinetic investigation of oral and IVdihydroergotamine in healthy subjects. Eur. J. Clin. Pharmacol. 1991;41:597-602). These results suggest that maximal receptor binding is notentirely necessary for the duration of clinical response.

As seen in FIGS. 3-5, the IV method of administration with the highC_(max) which resulted in side effects, showed extensive binding at thedopaminergic and adrenergic receptors at concentrations equivalent tothe peak plasma spikes (C_(max)) resulting from the IV administrationmethod. FIG. 4 shows receptor binding data at adrenergic (left panel)and dopaminergic (right panel) receptors, indicating greater response atseveral subtypes for intravenous administration at C_(max). The notation“(h)” represents cloned human receptor subtypes and “NS” indicatesnon-specific binding.

The dopaminergic receptors D1 and D2 are primarily responsible fornausea and emesis. Concentrations equivalent to the peak plasma spikes(C_(max)) resulting from the novel administration method that dampenedand delayed the peak, as shown in FIG. 2, significantly lowereddopaminergic receptor binding, specifically at D2 and D1, as shown inFIG. 4, with the ultimate result of reducing nausea and emesis in thepatients.

Similarly the lowered adrenergic binding shown in FIG. 4, correspondedto less vasoconstriction and lowered blood pressure or cardiovascularexcursions in the patients. While receptor binding at the adrenergic anddopaminergic receptors were lower at concentrations equivalent to thepeak plasma spikes (C_(max)) resulting from the novel administrationmethod, the binding achieved by these administration methods at theserotonin receptors, specifically 5HT_(1a/d) was sufficient to beefficacious for treatment of migraine. (FIG. 3.)

Agonists of 5-HT_(1B) subtype receptors are known to be useful in thetreatment of migraine and associated symptoms. 5-HT_(2B) receptors areknown to play a triggering role in the onset of migraine. FIG. 5 showsselective agonism at 5-HT_(1B) and 5-HT_(2B) receptors following highconcentration control (5 μm), IV at C_(max) (77.6 nM), 4 inhalations atC_(max) (6.25 nM) and at a markedly reduced concentration (0.25 nM).Whereas 5-HT_(1B) agonism is maintained across all concentrations,indicating high potency, agonism is absent for orally-inhaled DHE at the5-HT_(2B) receptors.

It is noted that all three methods of administration achieve rapidplasma levels within 20 minutes, with concentrations sufficient to bindthe serotonin receptors and effect rapid treatment of migraine. (FIG.2).

Example 4 Pulmonary Administration of DHE Formulations Using a TEMPO™Inhaler

DHE powder is generated using supercritical fluid processes which offersignificant advantages in the production of DHE particles for inhalationdelivery and produce respirable particles of the desired size in asingle step. (see WO2005/025506A2.) A property of processed DHE drugsubstance is that the supercritical fluid processed crystals haveremarkably smooth surfaces with low surface energies and therefore tendto disperse effectively in propellant based systems. A controlledparticle size for the microcrystals was chosen to ensure that asignificant fraction of DHE would be deposited in the lung.

A blend of two inert and non-flammable HFA propellants were selected aspart of formulation development) for the drug product: HFA 134a(1,1,1,2-tetrafluoroethane) and HFA 227ea(1,1,1,2,3,3,3-heptafluoropropane). The finished product contained apropellant blend of 70:30 HFA 227ea:HFA 134a, which was matched to thedensity of DHE crystals in order to promote pMDI suspension physicalstability. The resultant suspension did not sediment or cream (which canprecipitate irreversible agglomeration) and instead existed as asuspended loosely flocculated system, which is easily dispersed whenshaken. Loosely fluctuated systems are well regarded to provide optimalstability for pMDI canisters. As a result of the formulation'sproperties, the formulation contained no ethanol and nosurfactants/stabilizing agents.

The DHE formulation was administered to patients using TEMPO™, a novelbreath activated metered dose inhaler. TEMPO™ overcomes the variabilityassociated with standard pressurized metered dose inhalers (pMDI), andachieve consistent delivery of drug to the lung periphery where it canbe systemically absorbed. To do so, TEMPO™ incorporates four novelfeatures: 1) breath synchronous trigger—can be adjusted for differentdrugs and target populations to deliver the drug at a specific part ofthe inspiratory cycle, 2) plume control—an impinging jet to slow downthe aerosol plume within the actuator, 3) vortexing chamber—consistingof porous wall, which provides an air cushion to keep the slowed aerosolplume suspended and air inlets on the back wall which drive the slowedaerosol plume into a vortex pattern, maintaining the aerosol insuspension and allowing the particle size to reduce as the HFApropellant evaporates, and 4) dose counter—will determine the dosesremaining and prevent more than the intended maximum dose to beadministered from any one canister. Features 2 and 3 have been shown todramatically slow the deposition and improve lung deposition of theEmitted Dose (ED), by boosting the Fine Particle Fraction (FPF).

All publications and patent applications cited in this specification areherein incorporated by reference in their entirety as if each individualpublication or patent application is specifically and individuallyindicated to be incorporated by reference.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it will be readily apparent to those of ordinary skill inthe art in light of the teachings of this invention that certain changesand modifications may be made thereto without departing from the spiritor scope of the appended claims.

What is claimed is:
 1. A method of providing migraine therapy to a humansubject while minimizing one or more drug-induced side effects, saidmethod comprising: administering via pulmonary administration by oralinhalation a total dose of less than 3.0 mg of dihydroergotamine, or asalt thereof, to the human subject, wherein the dihydroergotamine, orsalt thereof, is administered at a rate that provides a mean peak plasmaconcentration (C_(max)) of dihydroergotamine of less than 20,000 pg/mlwithin a mean time to C_(max) (T_(max)) that is less than 20 minutesafter the administration; wherein the migraine therapy is prophylactic.2. The method of claim 1, wherein the human subject is suffering from atleast 2 headaches per month.
 3. The method of claim 1, wherein the humansubject is suffering from at least 4 headaches per month.
 4. The methodof claim 1, wherein the total dose of the dihydroergotamine, or saltthereof, ranges from 1.0 mg to 2.0 mg.
 5. The method of claim 1, whereinthe one or more side effects is selected from the group consisting ofnausea, emesis, vasospasm, paresthesia, hypertension, dizziness,anxiety, dyspnea, headache, flushing, diarrhea, rash, increasedsweating, cardiac valvulopathy, pleural and retroperitoneal fibrosis,adverse cardiovascular effect, blood pressure instability and arterialconstriction.
 6. The method of claim 5, wherein the one or more sideeffects is selected from the group consisting of nausea, emesis,paresthesia and dizziness.
 7. The method of claim 6, wherein the one ormore side effects is nausea, emesis or both.
 8. The method of claim 6,wherein the side effect is nausea.
 9. The method of claim 6, wherein theside effect is emesis.
 10. The method of claim 6, wherein the sideeffect is paresthesia.
 11. The method of claim 6, wherein the sideeffect is dizziness.
 12. The method of claim 1, wherein the C_(max) ofthe dihydroergotamine is less than 15,000 pg/ml.
 13. The method of claim1, wherein the C_(max) of the dihydroergotamine is less than 10,000pg/ml.
 14. The method of claim 1, wherein the C_(max) of thedihydroergotamine is less than 7,500 pg/ml.
 15. The method of claim 1,wherein the dihydroergotamine, or salt thereof, is administered by apressurized metered dose inhaler (pMDI).
 16. The method of claim 15,wherein the pMDI is a breath-activated pMDI.
 17. The method of claim 1,wherein the dihydroergotamine, or salt thereof, is administered withoutadministering an anti-emetic to the human subject.